RATIONALE: Panobinostat and imatinib mesylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PURPOSE: This phase I trial is studying the side effects and best dose of panobinostat when given together with imatinib in treating patients with previously treated chronic phase chronic myelogenous leukemia.

Patients receive oral panobinostat once daily on days 1, 3 and 5; 8, 10, and 12; 15, 17, and 19; and 22, 24, and 26. Patients also receive oral imatinib mesylate once daily on days 1-28. Treatment repeats every 21 or 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

Drug: imatinib mesylate

Given orally

Other Names:

CGP 57148

Gleevec

Glivec

Drug: panobinostat

Given orally

Other Names:

Faridak

HDAC inhibitor LBH589

histone deacetylase inhibitor LBH589

LBH589

Genetic: polymerase chain reaction

Testing

Genetic: protein expression analysis

Testing

Genetic: western blotting

Testing

Other: flow cytometry

Testing

Other: laboratory biomarker analysis

Testing

Other: pharmacological study

Testing

Detailed Description:

OBJECTIVES:

Primary

To determine the safety and tolerability of LBH589 given in combination with imatinib mesylate in CML patients who are in Major Cytogenetic Remission (MCR) with residual BCR-ABL positive cells after at least 1 year of daily imatinib mesylate treatment.

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity of LBH589 given in combination with imatinib mesylate in CML patients.

Secondary

To study the effect of LBH589 given in combination with imatinib mesylate on cytogenetic response status and BCR-ABL levels in CML patients in major cytogenetic remission on imatinib mesylate treatment.

Tertiary

To study the effect of LBH589 given in combination with imatinib mesylate on residual BCR-ABL positive primitive progenitors in CML patients in major cytogenetic remission on imatinib mesylate treatment.

OUTLINE: This is dose-escalation study of panobinostat.

Patients receive oral panobinostat once daily on days 1, 3 and 5; 8, 10, and 12; 15, 17, and 19; and 22, 24, and 26. Patients also receive oral imatinib mesylate once daily on days 1-28. Treatment repeats every 21 or 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month and then every 3 months for up to 1 year.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed

CML CP patients who have been treated with and tolerated Imatinib for 1 year or more, have achieved at least major cytogenetic response and continue to be BCR-ABL positive (Patients should be receiving Imatinib at a dose of 400 daily at the time of entry into the study)

Patient who have been treated with Imatinib < 1 year or patients are currently being treated with Imatinib at a dose > 400 mg daily

Impaired cardiac function including any one of the following: Screening ECG with a QTc > 450 msec; Patients with congenital long QT syndrome; History or presence of sustained ventricular tachycardia; Any history of ventricular fibrillation or torsades de pointes; Bradycardia defined as heart rate < 50 beats per minute (patients with a pacemaker and heart rate >= 50 beats per minute are eligible); Patients with a myocardial infarction or unstable angina within 6 months of study entry; Congestive heart failure (NY Heart Association class III or IV); Right bundle branch block and left anterior hemiblock (bifascicular block)

Uncontrolled hypertension

Concomitant use of drugs with a risk of prolonging the QT interval or inducing torsades de pointes

Concomitant use of CYP3A4 inhibitors

Patients with unresolved diarrhea > CTCAE grade 1

Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589

Other concurrent severe and/or uncontrolled medical conditions

Patients who have received chemotherapy, any investigational drug or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy

Concomitant use of any other anti-cancer therapy or radiation therapy

Patients being treated with Coumadin (unless patients who require anticoagulation can be switched to a low-molecular weight or standard heparin)

Female patients who are pregnant or breast feeding or patients of reproductive potential not willing to use a double method of contraception including a barrier method (i.e. condom) during the study and 3 months after the end of treatment (Women of childbearing potential [WOCBP] must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589)

Male patients whose sexual partners are WOCBP not willing to use a double method of contraception including condom during the study and 3 months after the end of treatment

Patients with a history of another primary malignancy within 5 years other than curatively treated CIS of the cervix, or basal or squamous cell carcinoma of the skin

Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required

Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00686218